Process for the preparation of 3-enol lower alkanoyl acylates of 17beta-acyloxy delta-androstene-3-one



PROGESSLFOKTHE; {PREPARATION-OF v3-ENOL' LOWER A CYLATES OF 1:7,8-ACYL- OXY M-ANDROSTENE-S-ONE Alberto Ercoli,'Milan, and Pietroile Ruggieri Casatenovo Brianz'ay'Italyysaid de Ruggierifassignor to Francesco VismaraSocieta per Azioniya company of Italy"v No Drawing;""ApplicationfJanuary 27, 1956 Serial No."56'1',949"

7. Claims. ,7 (Cl. 260-3975 This invention relates: to a new'method for preparing enol esters of A -3-ketosteroids and to a series ofsubstances which we have fou'ndto' be advantageous'start- I ing materials for the preparationof the same;

It is knoWn-'thatthe 3-enol 'esters'of ketosteroids are obtained, according :to the methods described in the chemical --literature,' by treating in a properniannerthe ketories having a free 3-carbonyl group with suitable'acylating agents.

We have now found that enol esters of A B-ketcsteroids' can be very advantageously obtained by treating thez-condensation derivatives of the enolic form of A -3-ketosteroids'with an organic acid anhydridein the presence of a'strong acid.

By the term condensation derivatives of the enolic form of A -3-ketosteroids, we mean-chiefly the products which may be considered deriving from the condensation of the t enolic form of A -3-ketosteroids' with'mono-and* bivalent alcohols-'and'with mono and bivalent "thio-alcohols, i; e. the enol ethers,the thioenol ethers andthe cyclic ketals andthioketals of A4-3-ketosteroids- I i We have noted indeed that these products, wherein the original A -3-ketogroup of the steroid have been' already converted into "a protectedenolic form," are very suitable starting materials for the '3-enol-esterificati0n:

In the practical use of ourinvention one" among the above-mentioned starting materials is contacted in the presence of a strongacid-with an excess of organic acid anhydride, diluted "with a 'suitabl'ezsolvent. 1

It is usually preferred touse as diluentan inert solvent, such v as aromatic or non aromatic,hydrocarbons, for example, benzene and homologues, 'cyclohexane and the like.

One may also.employ,as suitable diluents, halogenatedorganic solvents, as chloroform,*methylene'ch10 ride and the like, or theorganic acid' corresponding tothe' anhydride itself."

Among the strong acids we have found particularly suitabletheorganic sulfonic acids such as the benzene sulfonic, the p.toluenesulfonic, the naphthalenesulfonic,

the sulfosalicylic, the phenolsulfonic and anthraquinonsulfonic 'acids. Besides, the perchloric acid or also the Lewisacids, such as SnCl4, or SbCl ,-or AlCl may be advantageously employed;

The step of 3-.enol esterification, according to the present'inventiom-may be carried out at a temperature between the boiling point of the employed solventand 0 (3.; however at roomte'mperature or at about room temperature is more suitable for the formation of the desired 3-en-ol ester. This product is then isolated from the reac-' tion mixture by precipitation from its solution with'water, in which it is insoluble, or. also by extraction with a suitable solvent andevaporation thereof.

When in the above mentioned starting material another unprotected ketogroup is present," themethod "of the I pres'entinvention leads generallyv to the-selectiveiformation ofenol ester atthe C -position'.

Thus for example when the-3-enol benzyl ether of progesterone is subjected, according to our invention,- to

the action of acetic anhydride in the presence of astrong acid and this step is carried outat room temperature or about room'temperature, the only 3-enol acetate of progesterone is easily obtained. I Likewise by starting from the -3-enol ethyl ether of A -androstene-3,17-dione, by

treatment with acetic anhydride, suitably diluted with acetic'acid or benzene, in the presence of an organic sulfonic acid, the pure 3-enol-acetate of A -androstene-3,l7

dione melting at 137-139 is very simply prepared.

When the starting condensation derivative of the enolic form of the A -3-ketosteroid contains "inthe molecule one or alsoinore free hydroxyl groups, the method of the 3 present invention; besides leading to the formation of the' enol ester at 3 position, leads mostly also to the esterifica tionof the free hydroxyl groupv or groups. In such a manner it is possible to obtain the B-enoI-acetate of 17a,21- diacetate of cortisone by contacting the 3-enolethylether'of cortisone 21-acetate with acetic anhydride in the presence of p'.toluenesulfonic acid.

Furthermore if in the starting material already ester-' ified'hydroxyl groups are contained,--theyare notmodifled-by the S-enolesterification step carried out accord: ing to the present invention.- Thus, for instance, if the 3-enol ethyl ether of testosterone 17,6-phenylpropionate is treated with trimethylacetic anhydride, in the presence of Lewis acid or of an organic sulfonic acid, the 3 -enol trimethylacetate of testosterone 17,6-phenylpropionate is obtained. 7

The method of the present invention can also serve to directly convert, by one step, an enol ester of a N3- ketosteroid'into another enol ester of the same A -3- ketosteroid.

To this purpose if a 3-enol ester dissolved in a suitable diluent, is contacted, at room temperature and in the I presence ofa strong acid, with an organic acid anhydride,

another 3-enol ester is obtained, Wherein'the introduced acylic group corresponds to the-employed; anhydride. Thus, for instance, if the 3-enol-acetate "of 17-phenylpropionate of testosterone is treated, at roomt'emp'erature and in the presence of an organic sulfonic acid, withisobutyric anhydride, suitably diluted with isobutyric' acid or benzene, the 3-enol isobut-yrate of testosterone 17-phenylpropionate is easily obtained.

The following examples illustrate the invention, but

it is to be understood that the same are given-for purposes of illustration and'not of limitation.

Example 1 A solution of lg. of 3-enol-benzyl-ether of progesteronein 10 cc. of glacial acetic'acid and4cc. of acetic anhydride is treated-'wi'thl g. of snlfosalicylic acid'at room temperature for 3 hours; After dilution. with Water, the reaction mixture is cooled in ice-bath, and the'separatedproduct is' collected by filtration, washed with Water'and dried in the vacuum. The 3-en'ol-acetate of progesterone once crystallised from methanolmelts- This 'step'maybe carriedout employing as diluent instead of the glacial acetic'acid, the benzene or toluene.

Likewise, instead of sulfosalicylic acid, the perchloric acid or also a Lewisacid such as SnCl or SbCl may be advantageously used.

Example ,2

SOO-mgwof 3-.eno1-ethyl-etherof A -androstene-,3;l7- dione, dissolved in 10 cc. of anhydrousbenzene, are

Patented Aug. 12, 1958 treated with 3 cc. of acetic anhydride and 500 mg. of.

p.toluenesulfonic acid. After standing at room temperature for 3 hours, the benzene solution is washed at first with a diluted solution of alkali and then thoroughly with water, dried over sodium sulfate and the solvent evaporated in vacuo. The residue crystallised from methanol slightly diluted with water, yields 335 mg. (64% of the theoretical amounts) of 3-eno1-acetate of Ai-andros: tene-3,17-dione, M. P. 136-138".

The same result is reached by using as diluent instead of benzene, toluene or cyclohexane and by employing as strong acid, instead of the p.toluenesulfonic, another organic sulfonic acid such as the benzenesulfoni'c acid, and the naphthalene or anthraquinone a or B sulfonic acids.

Example 3 500 mg. of 3-ethyleneglycol ketal of n -androstene- 3,17-dione are dissolved in cc. of glacial acetic acid cortisone 21- 5 g. of cortisone 21-acetate are suspended in 100 cc.-

of anhydrous benzene and 40 cc. of the solvent are distilled in order to take out azeotropically eventual traces of moisture. To the remaining mixture brought up to 60 C. are added 5 g. of ethyl orthoformate, 2.56 cc. of absolute ethanol and 0.23 cc. of a 7% solution of hydrochloric acid in absolute ethyl alcohol. The heating is again maintained at about 60 C. for about one hour; during this period all the product passes into solu tion. The reaction mixture is then allowed to cool, 3 cc. of pyridine are added and the liquid is evaporated in the vacuum to dryness. The residue crystallised from methyl alcohol yields the 3-enol-ethyl-ether of cortisone 2l acetate, .M. P. 193.

Example 4 500 mg. of the 3-enol-ethyl-ether of cortisone 21- acetate, prepared as above described, are dissolved in cc. of acetic acid and treated with 5 cc. of acetic anhydride and 400 mg. of p.toluenesulfonic acid. After standing at room temperaturefor 3 hours, the solution is diluted with water and repeatedly extracted with ether; the collected ethereal extracts .are washed at first with dilutesodium carbonate solution and thenwith water to neutrality, dried over sodium sulfate and evaporated to dryness. The crystalline residue recrystallised from methanol containing a little water yields the 3-enolacetate of cortisone l7a,21-diacetate, M. P. 153154.

In essentially the same manner the 3-enol-acetate of the following compounds are prepared: the 3-enol-acetate of desoxycorticosterone 2l-acetate melting at .126-128, starting from 3-enol-benzyl-ether of desoxycorticosterone 21-acetate, M. P. 158-460"; the 3-enol-acetate of cortisone' 17a-21-diacetate melting at 151-153, starting from 3-enol-benzyl-ether of 21-acetate of cortisone, M. P. 204-205; the 3-enol-acetate of 17-B-acetoxy, l7-a-methyltestosterone melting at 99101, starting from 3-enol-benzyl-ether :of 17-a-methyltestosterone, M. P. 83-85 the 3-enol-acetate of 17-a-acetoxy testosterone melting at 198- 201, starting from 3-eno1-ethylether of testosterone, M. P; 119121.

Example 5 1 g. of 3-enol-ethyl-ether of testosterone l7-fi-phenylpropionate (prepared according to the process described in the continuation-impart Serial No. 497,388, filed March 23, 1955, to our copending application Serial No. 404,378, filed January 15, 1954) is dissolved in 10 cc. of isobutyric acid and 4 cc. of isobutyric anhydride. The solution is treated with 1 g. of p.toluenesulfonic acid for 3 hours at room temperature, it is then diluted with water and repeatedly extracted with ether; the ethereal extracts are collected, washed with diluted solution of alkali and with water, dried over sodium sulfate and evaporated in the vacuum. From the residue, crystallised twice from methanol, the 3-enolisobutyrate l7-fl-phenylpropionate of testosterone is obtained, M. P. -111.

Likewise if, always starting from 3-enol-ethyl-ether of testosterone l7-j3-phenylpropionate, the step is carried out with trirnethyla-cetic' anhydride, instead of the isobutyricone, the 3-enol-trimethyl-acetate of 17-B-phenylpropionate of testosterone is obtained, M. P. 106-109".

Analogously the 3-benzyl-thioenol ether of testosterone 17-5-phenylpropionate melting at 123125, by treatment with acetic anhydride and p. tuluene-sulfonic acid, yields the 3-enol-acetate of testosterone 17- 8-phenylpropionate, M. P. 90-92".

Example 6 500 mg. of 3-enol-acetate of 17-B-phenylpropionate of testosterone are dissolved in 10 cc. of isobutyric acid and treated with 4 cc. of isobutyric anhydride and 500 mg. of p.toluenesu] fonic acid. After standing at room.

temperature for 6 hours, the solution is then diluted with water and repeatedly extracted with ether; the ethereal layer is at first washed with diluted solution of alkali and then with water, dried over sodium sulfate and evaporated in the vacuum. From the residue, after one: crys-' tallisation from methanol, the 3-enol-isobutyrate 17-3- phenyl-propionate of testosterone is obtained, M. P. 109- 111.

What we claim is:

1. A process for the preparation of 3-venol lower alkanoyl acylates of 17/8-acyloxy A-4-androstene-3-one which comprises reacting at approximately room temperature a compound selected from the group consisting. of f (a) 3-enol lower alkyl ethers and benzyl ether and (b) 3-ethylene glycol ketal of 17,8-acyloxy A-4-androste'ne-3- one, wherein the acyl group is the radical .ofan organic carboxylic acid containing from one to' nine carbon atoms inclusive, with an anhydride of a lowertalkanoic acid, in the presence of a'strong acid selected from the group consisting of perchloric acid, Lewis acids and organic sulfonic acids to produce a -3-enol lower. alkanoyl acylate of -acyloxy-A-4-androstene-3-one.1 t

2. A process for the preparation of 3 enol lower alkanoyl acylates of 1713-acyloxy A-4-androstene-3-one which and organic sulfonic acids to produce a 3-enol lower.

alkanoyl acylate of 17B-acyloxy .A-4-androstene-3-one.

3. A process for the preparation of 3-enol lower alkanoyl acylates of 17p3-acyloxy A-4-androstene-3-one which comprises reacting at approximately room temperature a 3-ethylene glycol ketal of 17-,B-acyloxy A-4 ar1drostene-3- one wherein the acyl group is the radical of. an organic carboxylic acid containing from one. to nine carbon atoms inclusive, with'an anhydride of'a lower alkanoic acid, in the presence of a strong acid selected from the 5 group consisting of perchloric acid, Lewis acids and or- References Cited in the file of this patent ganic sulfonic acids to produce a 3-eno1 lower alkanoyl acylate of 17B-acy1oxy A-4-androstene-3-one. UNITED STATES PATENTS M 9 as defined in claim 1 wherein, the reac- 2,377,571 Nudenberg J 5, 1945 32 5 5 2 g i fi gz alkanmc and mnespondmg 5 2,416,024 Senkus Feb. 18, 1947 5. A process as defined in claim 1 wherein the reaction 2451434 i F 1948 is carried out in a liquid hydrocarbon. 2466738 Phllhps 1949 6. A process as defined in claim 1 wherein the reaction 2,673,867 Spem 1954 is carried out in a halogenated organic solvent. 10 2,697,108 Rosenbl'anz 1954 7. Aprocess as define-d in claim 1 wherein the 17fi-acyl 2,693,852 Beall 1955 group is B-phenylpropionyl. 

1. A PROCESS FOR THE PREPARATION OF 3-ENOL LOWER ALKANOYL ACYLATES OF 17B-ACYLOXY $-4-ANDROSTENE-3-ONE WHICH COMPRISES REACTING AT APPROXIMATELY ROOM TEMPERATURE A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) 3-ENOL LOWER ALKYL ETHERS AND BENZYL ETHER AND (B) 3-ETHYLENE GLYCOL KETAL OF 1MB-ACYLOXY $-4-ANDROSTENE-3ONE, WHEREIN THE ACYL GROUP IS THE RADICAL OF AN ORGANIC CARBOXYLIC ACID CONTAINING FROM ONE TO NINE CARBON ATOMS INCLUSIVE, WITH AN ANHYDRIDE OF A LOWER ALKANONIC ACID, IN THE PRESENCE OF A STRONG ACID SELECTED FROM THE GROUP CONSISTING OF PERCHLORIC ACID, LEWIS'' ACIDS AND ORGANIC SULFONIC ACIDS TO PRODUCE A 3-ENOL LOWER ALKANOYL ACYLATE OF 1MB-ACYLOXYL-$-4ANDROSTENE-3-ONE. 